Lignans Alleviate Depression by Modulating the Gut-Brain Axis: Effect and Mechanism Based on Multi-Omics Analyses

Area of Science:

• Neuroscience
• Microbiology
• Pharmacology

Background:

• Major depressive disorder (MDD) is a debilitating illness with poorly understood pathogenesis and limited effective treatments.
• The gut-brain axis and gut dysbiosis are increasingly recognized as critical factors in MDD development, contributing to neuro-inflammation.
• Current MDD therapies offer symptomatic relief but lack curative effects.

Purpose of the Study:

• To investigate the therapeutic potential of flaxseed lignans in ameliorating MDD.
• To evaluate the effects of flaxseed lignans on gut microbiome composition and function.
• To explore the impact of lignans on neuro-inflammation and the gut-brain axis in MDD.

Main Methods:

• Human participants with MDD were treated with flaxseed lignans to assess changes in disease severity and gut microbiota.
• An MDD mouse model was used to evaluate the behavioral, neural, and gut integrity effects of lignan treatment.
• Biochemical analyses were performed to measure levels of neurotransmitters (5-HT, BDNF, GABA), inflammatory markers, and signaling pathways (IL-17/AP-1/NF-κB).
• In vitro studies using BV-2 cells investigated the anti-inflammatory mechanisms of enterolactone, a specific lignan.

Main Results:

• Flaxseed lignans significantly reduced MDD severity and altered gut microbiota structure in human participants.
• In the MDD mouse model, lignans reversed depression-like behaviors, repaired neural and gut damage, and restored barrier integrity.
• Lignan treatment increased levels of 5-HT, BDNF, and GABA, while significantly reducing microglial and systemic inflammation.
• Mechanistically, lignans inhibited the IL-17/AP-1/NF-κB axis by interacting with Fos protein and reduced pro-inflammatory cytokines in BV-2 cells.

Conclusions:

• Flaxseed lignans demonstrate potent antidepressant effects by modulating the gut-brain axis and resolving neuro-inflammation.
• These findings suggest lignans can restore gut micro-environmental functionality and alleviate MDD symptoms.
• Flaxseed lignans represent a promising therapeutic strategy for MDD prevention and treatment, offering a novel approach targeting the gut-brain axis.